Neurodegenerative disorders are hereditary and sporadic conditions which are characterized by progressive nervous system dysfunction. These disorders are often associated with atrophy of the affected central or peripheral structures of the nervous system. They include diseases such as Alzheimer's Disease and other dementias, Brain Cancer, Degenerative Nerve Diseases, Encephalitis, Epilepsy, Genetic Brain Disorders, Head and Brain Malformations, Hydrocephalus, Stroke, Parkinson's Disease, Multiple Sclerosis, Amyotrophic Lateral Sclerosis (ALS or Lou Gehrig's Disease), Huntington's Disease, Prion Diseases, polyneuropathy, and others. Interventions include preventative measures, lifestyle changes, physiotherapy or other therapy, neuro-rehabilitation, pain management, medication, or operations performed by neurosurgeons (WHO Neurological Disorders: Public Health Challenges, 2006).
Axonal degeneration is a common hallmark of many neurodegenerative diseases. A longstanding clinical observation is the tendency for demyelinated nerve fibers to undergo degeneration and loss. There is now a wealth of evidence that demyelination contributes to altered axonal transpmi, axonal degeneration, and loss (de Waegh et al., 1992; Trapp et al., 1998; Coleman and Perry, 2002; Ciccarelli et al., 2003; Oh et al., 2004). Examples include heritable demyelinating diseases of both the CNS and PNS. Many of the genetic defects in these diseases are abnormalities in genes encoding intrinsic myelin proteins and not expressed in axons. The clinical manifestations are often attributable to progressive, distally predominant axonal degeneration (Berciano et al., 2000; Krajewski et al., 2000).
The myelin-associated glycoprotein (MAG) is a component of all myelinated internodes. MAG is a transmembrane glycoprotein containing five Ig-like domains in its extracellular domain. It is an adhesion molecule belonging to the immunoglobin superfamily. MAG is distinctively located in the adaxonal plasmalemma that apposes the axon as well as the paranodal loops, Schmidt-Lanterman incisures, and mesaxons (Trapp and Quarles, 1982). The normal role of MAG is not well understood. MAG is not necessary for myelination, and myelin sheaths of MAG knock-out mice (MAG−/−) are largely normal (Yin et al., 1998). Its distribution has prompted the hypothesis that MAG prevents compaction of myelin membranes and contributes to the uniform intermembranous distance characteristic of the periaxonal space (Trapp and Quarles, 1982). MAG is known to signal to the axon, locally influencing the phosphorylation of 20 axonal neurofilaments immediately beneath MAG-bearing membranes because of reduced interfilament spacing (Hsieh et al., 1994; Dashiell et al., 2002). Myelinated axons of MAG −/− mice have smaller diameters than normal as a result of hypophosphorylation of the neurofilament proteins NF—H and NF-M (Garcia et al., 2003; Rao et al., 2003).
Much of the published research on MAG has focused on its ability to inhibit axonal growth and elongation during regeneration. Multiple axonal receptors have been proposed to mediate MAG-induced growth cone collapse. One is a multicomponent complex consisting of a ligand-binding Nogo-66 receptor (NgR) and two transmembrane coreceptors, LINGO-1 and either p75 or TROY (Fournier et al., 2003; Mi et al., 2004). A second is proposed to be gangliosides GD1a and GT1b. Interaction of MAG with axons involves at least two recognition sites on MAG: one around arginine 118 (R118) in Ig domain 1 and second in Ig domains 4 and 5 (Kelm et al., 1994; Tang et al., 1997; Cao et aL, 2007). Whereas Ig domains 4 and 5 are believed to be important for the interaction with NgR, the R118 binding site is thought to involve in interactions with gangliosides. Other roles of MAG at the R118 binding site remain unclear.
MAG−/− mice develop axonal loss in the CNS and PNS (Yin et aL, 1998; Pan et al., 2005) suggesting that MAG may influence axonal maintenance. A recent study indicated that MAG promotes axonal stability and survival in cell culture and in vivo (Nguyen et al., 2009). This study showed that MAG signals to the axon to promote stability of axonal microtubules, and promotes axonal survival in the face of insults such as vincristine, acrylamide, and inflammatory mediators. The effect of MAG on axonal stability is independent of Nogo signaling in the axon and depends on the arginine 118 residue in the RGD (Arginine-Glycine Aspartate) domain of the extracellular segment of the molecule. An R118-mutated MAG failed to prevent axonal degeneration caused by vincristine. This suggested that MAG-induced axonal protection depends on the functional binding site around arginine 118.
Despite the axon protective abilities of MAG, its potential as a candidate drug in the treatment of neurodegenerative disorders is limited due to its high molecular weight which makes it unable to cross the blood-brain barrier in patients. There continues to be a pressing need in the art for novel therapies and molecules that exhibit neuronal. and axonal protective effect and are effective in vivo, crossing the plasma membrane and the blood-brain barrier.